The Discovery Core will utilize virtual and convenfional screening approaches to identify small molecules that modulate GPCR interactions with G proteins, GRKs and p-arrestins. In addition, a human lenfiviral shRNA library will be screened for effects on cAMP producfion, Ca^* flux, and steroid sensitivity in human airway smooth muscle cells. Small molecule and lenfiviral library screening will be conducted in the KCC Discovery Core at Thomas Jefferson University (http://www.kimmelcancercenter.orq/kcc/kccnew/research/resources/discoverv/). which provides liquid handling and optical detection for high-throughput screening of arrayed libraries of small molecules, as well as shRNA transducfion and target identification capabilities. Assays for arrayed library screening include cAMP-Glo and EPAC for cAMP quantification, Fura2/AM for Ca^* flux and BRET^ to quantify p-arrestin recruitment. The Discovery Core maintains several compound collections, including the US Drug Collection from Microsource Diversity and the Diverset and CNS libraries from Chembridge, and can array small molecule libraries that are acquired from public or private entifies, or that are suggested through virtual screening efforts. Since several GRKs have been characterized by X-ray crystallography, it is also possible to perform virtual screening using computational modeling and docking approaches. These models will be evaluated and refined with an all-atom physics-based potenfial function approach using CHARMM for energy minimization, refinement, conformational sampling and dynamics. CHARMM-based molecular docking and scoring approaches will be used to predict relevant GRK-small molecule interacfions. RELEVANCE (See instructions): These studies should identify small molecules that will be able to enhance relaxation or inhibit constriction of human airway smooth muscle. These molecules should serve as good leads for the development of more effective treatments of human airway diseases such as asthma.